Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/04—Linear peptides containing only normal peptide links
  • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/64—Cyclic peptides containing only normal peptide links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/14—Extraction; Separation; Purification
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
  • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
  • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the present invention relates to a pharmaceutical composition, and more particularly to a pharmaceutical composition of a hydrate of a cyclic peptide compound having good stability, a process for the preparation thereof and use thereof. Background technique
• Fungal infections have become a major cause of high morbidity and mortality in immunodeficient patients. In the past 20 years, the incidence of mold infection has increased significantly. High-risk populations of fungal infections include critically ill patients, surgical patients, and those with HIV infection, blood cancer, and other oncological diseases. Those who have been transplanted by organs are also at high risk of fungal infections.
• Echinoglobin is a new class of antifungal agents that works well for treating infections caused by Candida or Aspergillus. These drugs are represented by caspofungin and micafungin. Echinoglobin inhibits fungi by inhibiting the formation of 1, 3-beta glycosidic bonds, thereby reducing harm to the human body, reducing side effects as much as possible while efficient, so they are in use Safer than traditional antifungal drugs.
• FK463 also known as micafungin sodium
• R is sodium ion
• F 901379 as the compound of formula I II (R is sodium ion or hydrogen ion) as a precursor to remove the side chain by enzyme to obtain FR179642, as shown in formula I, (R is hydrogen ion or sodium ion
• Formula I Formula I
• the inventors have found through extensive research that the water content of the hydrate of the compound of formula I has an important influence on the stability of the compound of formula I. More surprisingly, the high moisture content of the compound of formula I not only does not accelerate the decomposition of the compound of formula I, but the stability of the compound of formula I is degraded, which in turn effectively increases the stability of the compound of formula I. As described above, when the moisture content of the compound of the formula I is less than 8%, the stability of the compound of the formula I is remarkably deteriorated. At the same time, the inventors have also found that the stability of the compound of formula I has little to do with the type of crystal form, and the moisture content is a crucial factor determining the stability of the compound of formula I. This is unexpected to many people, and it is also the conclusion of the inventor after a lot of experimental research.
• the invention provides a hydrate of a compound of formula I, R represents H or is pharmaceutically acceptable a cation capable of forming an addition salt, characterized in that the mass percentage of water in the hydrate is greater than 8.0%; R is preferably H, sodium ion or diisopropylethylamine ion;
• the mass percentage of water comprises J: from 8% to 30%.
• the mass percentage of the water comprising: 9.5% to 28 ⁇ 0 0 / ⁇ .
• the hydrate is produced by the following steps:
• the organic solvent (i) is selected from the group consisting of C1-C4 lower alcohols.
• the lower alcohol is selected from one or more of the group consisting of methanol, ethanol, n-propanol, and isopropanol.
• the controlled solids have a mass percentage of water greater than 8%.
• the controlled solids have a mass percentage of water of from 8% to 30%. In still further embodiments, the controlled mass percentage of water in the solid is 9.5% to
• the invention provides a method of preparing a hydrate of a compound of formula I, the method comprising the following steps:
• step (d) Vacuum drying the hydrate obtained in the step (C) to control the mass percentage of water in the hydrate.
• the organic solvent (i) is selected from the group consisting of C1-C4 lower alcohols.
• the lower alcohol is selected from one or more of the group consisting of methanol, ethanol, n-propanol, and isopropanol.
• the controlled solids have a mass percentage of water greater than 8%.
• the controlled mass of water in the solids is from 8% to 30%. In still further embodiments, the controlled mass percentage of water in the solid is from 9.5% to 28.0%.
• the invention provides the use of a hydrate as described above for the manufacture of a medicament for the treatment of a fungal infection.
• the present invention provides a pharmaceutical composition comprising the above hydrate and a pharmaceutically acceptable carrier.
• the present invention provides a method of preparing the above pharmaceutical composition comprising: mixing the above hydrate with a pharmaceutically acceptable carrier to obtain the above pharmaceutical composition.
• the invention provides a hydrate prepared by the above process.
• Figure 1 is an HPLC chart of the hydrate D in Example 2 after standing at 25 ° C for 6 months.
• FIG. 2 is an HPLC chart of the hydrate Y in Example 6 after standing at 25 ° C for 6 months.
• Figure 3 shows the sample impurity levels of hydrates, B, C, D and E after standing at 25 ° C for 6 months.
• Figure 4 is a hydrate? The impurity content of the samples after G, H, I and J were placed at 25 ° C for 6 months.
• Figure 5 shows the impurity content of the sample after hydrate, L, M, N and 0 were placed at 25 ° C for 6 months.
• Figure 6 is a hydrate?
• the impurity content of the samples after Q, R, S and T were placed at 25 ° C for 6 months.
• Figure 7 shows the impurity content of the samples after the hydrates U, V, W, X and Y were placed at 25 ° C for 6 months.
• the inventors have conducted extensive experimental studies and found that the compound of formula I is dissolved in a mixed solution of water or a water-miscible organic solvent, and the solution containing the compound of formula I is maintained near the saturation solubility, at which time the pH of the solution is controlled. Within the specified range, a hydrate of the compound of formula I can be obtained. More importantly, the hydrate formed by the compound of Formula I contains water, and the inventors have found through extensive studies that the water content of the hydrate of the compound of Formula I has an important influence on the stability of the hydrate formed.
• the preparation method has done a lot of detailed work on the screening of the crystallization solvent, wherein it is crystallized in methanol, ethanol, n-propanol, isopropanol or a mixed solution, and the compound of the formula I forms a crystal having excellent morphology, and controls the content thereof.
• the amount of water in a certain range gives a compound of the formula I which is excellent in stability.
• crystallized in a solvent such as acetone, acetonitrile or ethyl acetate
• the compound of the formula I forms an amorphous precipitate, and the stability is also deteriorated, which is also the difference in the stability of the amorphous solid substance and the crystalline substance.
• the pH control range is another key parameter for the ability of the compound of formula I to be a crystalline form to increase stability. Above the pH range, the morphology of the material changes to an amorphous direction.
• the term "effective amount" refers to a carrier for the administration of a therapeutic agent, including various excipients and diluents.
• the term refers to pharmaceutical carriers which are not themselves essential active ingredients and which are not excessively toxic. Suitable carriers are well known to those of ordinary skill in the art. In Remington's Pharmaceutical Sciences
• the pharmaceutically acceptable carrier in the composition may include liquids such as water, saline, glycerin and ethanol.
• auxiliary substances such as disintegrants, wetting agents, emulsifiers, pH buffering substances and the like may also be present in these carriers.
• compositions can be prepared in a variety of dosage forms depending on the route of administration. These dosage forms are administered in the following manner: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, and intracranial Inject or enter, or use an explant reservoir.
• R represents a cation of H.
• the pharmaceutically acceptable salts preferably include: metal salts such as alkali metal salts (e.g., sodium salts, potassium salts), alkaline earth metal salts (e.g., calcium salts, magnesium salts, etc.), ammonium salts, salts with organic bases (e.g., trimethylamine).
• metal salts such as alkali metal salts (e.g., sodium salts, potassium salts), alkaline earth metal salts (e.g., calcium salts, magnesium salts, etc.), ammonium salts, salts with organic bases (e.g., trimethylamine).
• Salt triethylamine salt, pyridinium salt, methylpyridine salt, dicyclohexylammonium salt, hydrazine, ⁇ '-dibenzylethylenediamine salt, diisopropylethylamine salt, etc., organic acid addition salt (such as formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, besylate, tosylate, etc.), inorganic acid addition salts (such as hydrochloric acid) Salt, hydrobromide, hydroiodide, sulfate, phosphate, etc.), salts with amino acids (such as arginine, aspartic acid, glutamic acid, etc.); R is most preferably strontium, sodium ion Or diisopropylethylamine ion.
• organic acid addition salt such as formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, bes
• the compound of formula I can be obtained by methods conventional in the art, such as, but not limited to, the preparation of the compound as reported in patent WO9611210; it is also commercially available, such as, but not limited to, for example, Fujisawa Corporation of Japan.
• lower alcohol of C1-C4 means an alcohol having from 1 to 4 carbon atoms.
• the inventors have found through intensive studies that the compound of formula I is dissolved in a mixed solution of water or a water-miscible organic solvent, and the solution containing the compound of formula I is maintained in the vicinity of saturated solubility, at which time the pH of the solution is controlled. Within the specified range, a stable hydrate of the compound of formula I is obtained by changing the crystallization temperature, molar concentration, cooling rate or stirring, crystallization time and the like by vacuum drying.
• the present invention provides a stable hydrate of a compound of formula I wherein the mass percentage of water is greater than 8.0%; more preferably from 8.0% to 30%; most preferably from 9.5% to 28%.
• the present invention provides a process for the preparation of a hydrate of the compound of formula I, which process comprises the steps of:
• step (d) Vacuum drying the solid obtained in step (c) to control the mass percentage of water in the hydrate.
• the dissolution temperature in the step (a) is from 10 to 50 ° C, preferably from 20 to 40 V.
• the ratio of the organic solvent (i) is 0. 1 to 10, more preferably 0.5 to 3. 0.
• the total volume of the solution as described in the step (a) contains 10 to 500 mg/ml, preferably 100 to 400 mg/ml, of the compound of the formula I.
• the pH of the solution in the step (a) is controlled at 2. 0-5. 0, preferably 3. 5_4. 5.
• the temperature of the cooling described in the step (b) is -40 to 35 °C, preferably -10 to 35 °C, more preferably -5 to 30 V, and most preferably 5 to 10 °C.
• the volume ratio of the organic solvent (i) in the step (b) to the solution in the step (a) is from 0.1 to 10, preferably from 1 to 5.
• organic solvent (i) described in the step (a) and the Z or (b) is a C1-C4 lower alcohol; preferably from: one or more of methanol, ethanol, n-propanol, isopropanol mixture.
• the mass percentage of water in the solid in step (d) is controlled to be greater than 8.0%, more preferably between 8. 0% and 30%, and optimally controlled at 9.5% to 28%.
• the hydrate can be separated by filtration, decanting of the solvent, or other means, preferably by filtration. The hydrate can then optionally be washed, and finally the hydrate is dried under vacuum to give a hydrate of the compound of formula I.
• the following procedure is employed to obtain a hydrate of a compound of formula I:
• step (d) Vacuum drying step (c) The solid obtained is used to control the mass percentage of water in the hydrate; wherein the temperature of the dissolution described in the step (a) is 10 to 50 ° C, preferably 20 to 40 t.
• the total volume of the solution in the step (a), wherein the compound 10 is as shown in formula I 500 mg/ml, preferably 100 to 400 mg/ml.
• the pH of the solution in the step (a) is controlled at 2. 0-5. 0, preferably 3. 5_4. 5.
• the temperature of the cooling described in the step (b) is -40 to 35 ° C, preferably -10 to 35 ° C, more preferably
• the mass percentage of water in the solid in step (d) is controlled to be greater than 8.0%, more preferably between 8. 0% and 30%, and optimally controlled at 9.5% to 28%.
• the following procedure is employed to obtain a hydrate of a compound of formula I:
• step (d) Vacuum drying step (c) The solid obtained is used to control the mass percentage of water in the hydrate; wherein the temperature of the dissolution in the step (a) is 10 to 50 ° C, preferably 20 to 40 V.
• the total volume of the solution as described in the step (a) contains 10 to 500 mg/ml, preferably 50 to 30 Q mg/ml, of the compound of the formula I.
• the pH of the solution in the step (a) is controlled at 2. 0-5. 0, preferably 3. 5_4. 5.
• the organic solvent (i) described in the step (b) is a C1-C4 lower alcohol; preferably from: a mixture of one or more of methanol, ethanol, n-propanol and isopropanol.
• the volume ratio of the organic solvent (i) in the step (b) to the solution in the step (a) is from 0.1 to 10, preferably from 1 to 5.
• the mass percentage of water in the solid in step (d) is controlled to be greater than 8.0%, more preferably between 8. 0% and 30%, and optimally controlled at 9.5% to 28%.
• the following procedure is employed to obtain a hydrate of a compound of formula I: (a) A compound of formula I is dissolved in water to control the pH of the solution.
• step (d) vacuum drying the solid obtained in the step (c), controlling the mass percentage of water in the hydrate; wherein the temperature of the dissolution described in the step (a) is 10 to 50 ° C, preferably 20 to 40 ° C .
• 500 mg/ml preferably 50 to 300 mg/ml.
• the pH of the solution in step (a) is controlled at 2. 0-5. 0, preferably 3. 5_4.
• the organic solvent (i) described in the step (b) is a C1-C4 lower alcohol; preferably from a mixture of one or more of methanol, ethanol, n-propanol and isopropanol.
• the temperature of the cooling described in the step (b) is -40 to 35 ° C, preferably -10 to 35 ° C, more preferably
• the volume ratio of the organic solvent (i) in the step (b) to the solution in the step (a) is from 0.1 to 10, preferably from 1 to 5.
• the mass percentage of water in the solid in step (d) is controlled to be greater than 8.0%, more preferably at 8.0% to 30%, and optimally controlled at 9.5% to 28%.
• the following procedure is employed to obtain a hydrate of a compound of formula I:
• step (d) Vacuum drying step (c) The solid obtained is used to control the mass percentage of water in the hydrate; wherein the temperature of the dissolution in the step (a) is from 10 to 50 ° C, preferably from 20 to 40 V.
• the aqueous solution of the organic solvent (i) in the step (a) has a volume ratio of the organic solvent (i) to water of from 0.01 to 100, preferably from 0.1 to 10, more preferably from 0.5 to 3.0.
• the total volume of the solution as described in the step (a) contains 10 to 500 mg/ml, preferably 100 to 400 mg/ml, of the compound of the formula I.
• the pH of the solution described in the step (a) is controlled to be 2.0 to 5.0, preferably 3.5 to 4.5.
• the organic solvent (i) described in the step (a) is a C1-C4 lower alcohol; preferably from: a mixture of one or more of methanol, ethanol, n-propanol and isopropanol.
• the temperature of the cooling described in the step (b) is -40 to 35 °C, preferably -10 to 35 °C, more preferably -5 to 30 V, and most preferably 5 to 10 °C.
• the mass percentage of water in the solid in step (d) is controlled to be greater than 8.0%, more preferably at 8.0% to 30%, and optimally controlled at 9.5% to 28%.
• the following procedure is employed to obtain a hydrate of a compound of formula I: (a) a compound of formula I is dissolved in an aqueous solution of an organic solvent (i) to control the pH of the solution. .
• step (d) Vacuum drying step (c) The solid obtained is used to control the mass percentage of water in the hydrate; wherein the temperature of the dissolution described in the step (a) is 10 to 50 ° C, preferably 20 to 40 V.
• the aqueous solution of the organic solvent (i) in the step (a) has a volume ratio of the organic solvent (i) to water of from 0.01 to 100, preferably from 0.1 to 10, more preferably from 0.5 to 3.0.
• the total volume of the solution described in the step (a) contains 10 to 500 mg/ml, preferably 100 to 400 mg/ml, of the compound of the formula I.
• the pH of the solution described in the step (a) is controlled to be 2.0 to 5.0, preferably 3.5 to 4.5.
• the volume ratio of the organic solvent (i) in the step (b) to the solution in the step (a) is from 0.1 to 10, preferably from 1 to 5.
• the organic solvent (i) described in the steps (a) and (b) is a C1-C4 lower alcohol; preferably from: a mixture of one or more of methanol, ethanol, n-propanol, isopropanol .
• step (d) Vacuum drying the solid obtained in step (c) to control the mass percentage of water in the hydrate; wherein the temperature of the dissolution in the step (a) is from 10 to 50 ° C, preferably from 20 to 40 V.
• the ratio of the organic solvent (i) is 0. 1 to 10, more preferably 0.5 to 3. 0
• the total volume of the solution described in the step (a) contains 10 to 500 mg/ml of the compound of the formula I, preferably 100 to 400 mg/ml.
• the pH of the solution in the step (a) is controlled at 2. 0-5. 0, preferably 3. 5_4. 5
• the temperature of the cooling described in the step (b) is -40 to 35 ° C, preferably -10 to 35 ° C, more preferably -5 to 30 V, and most preferably 5 to 10 ° C.
• volume ratio of the organic solvent (i) in the step (b) to the solution in the step (a) is from 0.1 to 10, preferably from 1 to 5
• organic solvent (i) described in the steps (a) and (b) is a C1-C4 lower alcohol; preferably from: one or more of methanol, ethanol, n-propanol, isopropanol mixture.
• the mass percentage of water in the solid in step (d) is controlled to be greater than 8. 0%, more preferably in the range of 8. 0% - 30%, optimally controlled at 9. 5% - 28% Nature
• the present inventors further studied the properties of the compound of the formula I after obtaining the hydrate of the compound of the formula I by various means and instruments.
• the mass percentage of water in the composition is determined using a detection method common in the art. For example, Karl Fischer (KF) is used to determine the moisture content.
• Karl Fischer Karl Fischer
• the purity of the sample prepared by the method of the present invention and the stability study for the sample are measured by HPLC, and the HPLC detection method is as follows:
• Mobile phase A: 1000 ml water, 10 ml methanol, 100 ⁇ trifluoroacetic acid
• the hydrate of the compound of the formula I of the present invention is stable, is convenient for industrial production, and is advantageous for long-term preservation.
• the inventors have determined through stability tests that the hydrate of the compound of formula I prepared by the process of the invention has good stability. It can be stored at 25 °C for a long time, and it also solves the transportation problem of raw materials.
• the product When the moisture content is less than 8.0%, the product is stored at 0-8 °C for a long time, only slight degradation occurs; but the product is stored at 25 °C for a long time, the stability of the product is significantly reduced, and the product undergoes significant degradation. .
• a hydrate of a compound of formula I is provided.
• it can be used to prepare compounds of formula II; synthetic routes are reported in various patents, for example, WO961 1210, US6291680, WO2004014879, and the like.
• the present invention can also provide a pharmaceutical composition comprising a hydrate of a compound of the formula I and a pharmaceutically acceptable carrier.
• the main advantages of the present invention are as follows: 1.
• the present invention has selected unexpected preparation conditions by repeated experiments on the preparation conditions, and has produced unexpected technical effects, and provides a highly stable preparation of the compound of the formula I hydrate.
• the method, and the method is very suitable for large scale production.
• the hydrate of the compound of the formula I of the present invention is excellent in stability, and is remarkably superior to the compound of the formula I in which the mass percentage of water is less than 8.0% and the compound of the formula I prepared by the prior art.
• the unit in the weight percent by volume in the present invention is well known to those skilled in the art and, for example, refers to the weight of the solute in a 100 ml solution.
• a solid powder of the compound of formula I is prepared by the method of Example 1 with reference to U.S. Patent 5,376,634.
• the Karl Fischer method was used to determine the moisture content of the compound of formula I at 3.4%.
• the 2.0 g sample obtained above was taken for stability study. The method is as follows: sealed at 0-8 ° C for 6 months, and sealed at 25 ° C for 6 months, and then analyzed the impurity content of the sample.
• the starting impurity content of the compound of formula I was 2.4%
• the impurity content of the sample at 0-8 ° C for 6 months was 3.0%
• the impurity content of the sample at 25 ° C for 6 months was 4.9%.
• the remaining sample was further dried for 1.5 hours, and a hydrate of 1.0 g was obtained, which was named hydrate D of the compound of the formula I, and the mass percentage of water in D was found to be 9.5%.
• Phosphorus pentoxide was placed in a vacuum drying oven, and the remaining sample was further dried for 2 hours to obtain a hydrate of 1.0 g, which was named hydrate E of the compound of formula I, and the mass percentage of water in E was measured to be 6.1%. .
• the samples obtained above were subjected to stability studies.
• the method is as follows: hydrate A, hydrate B, hydrate C, hydrate D, hydrate E, respectively, sealed at 0-8 ° C for 6 months, and sealed at 25 ° C for 6 Months, then analyze the impurity content of the sample.
• the remaining sample was further dried for 2 hours, and a hydrate of 1.0 g, designated as the hydrate I of the compound of the formula I, was measured, and the mass percentage of water in the I was determined to be 8.6%.
• Phosphorus pentoxide was placed in a vacuum oven, and the sample was allowed to continue to dry for 1 hour.
• a hydrate of 1.0 g was obtained, and a hydrate J of the compound of the formula I was named, and the mass percentage of water in J was determined to be 7.2%.
• the stability results are as follows:
• a hydrate of 1.0 g designated as the hydrate K of the compound of the formula I, was found to have a mass percentage of water of 29.5%.
• the remaining sample was further dried for 0.5 hours, and a hydrate of 1.0 g, designated as a hydrate L of the compound of the formula I, was found to have a mass percentage of water of 27.5%.
• the remaining sample was dried for 3 hours, and a hydrate of 1.0 g was obtained, and a hydrate M of the compound of the formula I was named, and the mass percentage of water in M was 19.8%.
• the remaining sample was further dried for 4 hours, and a hydrate of 1.0 g was obtained, which was named as a hydrate N of the compound of the formula I, and the mass percentage of water in the N was determined to be 9.6%.
• Phosphorus pentoxide was placed in a vacuum drying oven, and the remaining sample was further dried for 4 hours to obtain a hydrate of 1.0 g, which was named as a hydrate of the compound of the formula I, and the mass percentage of water in the mixture was determined to be 4.9%.
• the compound of the formula I obtained in Example 1 was dissolved in a mixed solution of 40 ml of water and 64 ml of methanol at 25 ° C, and stirred for 2 hours to completely dissolve the compound of the formula I.
• the glacial acetic acid was adjusted to pH 3.5, and 300 ml of methanol was slowly added, and the hydrate of the compound of the formula I was precipitated. Filtration provides the hydrate of the compound of formula I.
• the hydrate of the compound of the formula I was dried under vacuum at 20 ° C to 25 ° C for 2 hours. After drying for 0.5 hours, a hydrate of 1.0 g, designated as the hydrate P of the compound of the formula I, was found to have a mass percentage of water of 31.3%.
• the remaining sample was further dried for 0.5 hours, and a hydrate of 1.0 g was obtained, which was named as a hydrate Q of the compound of the formula I, and the mass percentage of water in the Q was determined to be 27.3%.
• the remaining sample was further dried for 3 hours, and a hydrate of 1.0 g was obtained, which was named hydrate R of the compound of the formula I, and the mass percentage of water in R was measured to be 19.0%.
• the remaining sample was further dried for 4 hours, and a hydrate of 1.0 g was obtained, and the hydrate S of the compound of the formula I was named, and the mass percentage of water in the S was measured to be 9.0%.
• Phosphorus pentoxide was placed in a vacuum oven, and the sample was allowed to continue to dry for 1 hour.
• the hydrate L0 g was designated as the hydrate T of the compound of the formula I, and the mass percentage of water in the mash was measured to be 8%.
• a hydrate of 1.0 g designated as the hydrate U of the compound of the formula I, was measured, and the mass percentage of water in the U was measured to be 42.0%.
• the remaining sample was further dried for 2 hours, and a hydrate of 1.0 g was obtained, which was named hydrate V of the compound of the formula I, and the mass percentage of water in the V was measured to be 30.0%.
• the remaining sample was further dried for 2 hours, and a hydrate of 1.0 g, designated as a hydrate W of the compound of the formula I, was found to have a mass percentage of water of 19.5%.
• Phosphorus pentoxide was placed in a vacuum oven, and the sample was left to dry for 2 hours.
• a hydrate of 1.0 g was obtained, and a hydrate X of the compound of the formula I was designated.
• the mass percentage of water in the X was determined to be 9.6%.
• Phosphorus pentoxide was placed in a vacuum oven, and the sample was allowed to continue to dry for 2 hours.
• a hydrate of 1.0 g was obtained, and a hydrate Y of the compound of the formula I was named, and the mass percentage of water in the mash was 1.9%.
• the remaining sample was further dried for 3.5 hours, and a hydrate of 1.0 g, designated as the hydrate b of the compound of the formula I, was found to have a mass percentage of water of 17.5%.
• Phosphorus pentoxide was placed in a vacuum drying oven, and the remaining sample was further dried for 3 hours to obtain a hydrate of 1.0 g, which was named hydrate c of the compound of the formula I, and the mass percentage of water in the c was determined to be 6.3%.
• the hydrate of the compound of the formula I has an excellent stability at a moisture content of from 8.0% to 30%.
• the hydrate content of the compound of formula I is above 30% or below 8.0%, and the hydrate stability of the compound of formula I is significantly reduced.
• Example 9 Preparation of hydrates containing compounds of formula I, g, h, i (pH effect)
• the remaining sample was further dried for 4 hours, and a hydrate of 1.0 g was obtained, which was named as a hydrate h of the compound of the formula I, and the mass percentage of water in the h was measured to be 14.5%.
• Phosphorus pentoxide was placed in a vacuum drying oven, and the remaining sample was further dried for 4 hours to obtain a hydrate of 1.0 g, which was designated as a hydrate i of the compound of the formula I, and the mass percentage of water in the i was determined to be 6.3%.
• the remaining sample was further dried for 4 hours, and a hydrate of 1.0 g was obtained, which was named as the hydrate k of the compound of the formula I, and the mass percentage of water in k was 14.1%.
• Phosphorus pentoxide was placed in a vacuum drying oven, and the remaining sample was further dried for 4 hours to obtain a hydrate of 1.0 g, which was designated as a hydrate of the compound of the formula I, and the mass percentage of the water in the water was determined to be 6.6%.
• the remaining sample was further dried for 4 hours, and a hydrate of 1.0 g, a hydrate of the compound of the formula I, was found, and the mass percentage of water in n was determined to be 18.1%.
• Phosphorus pentoxide was placed in a vacuum drying oven, and the remaining sample was further dried for 4 hours to obtain a hydrate of 1.0 g, which was named as a hydrate o of the compound of the formula I, and the mass percentage of water in the mixture was determined to be 10.2%.
• the stability results are as follows:
• the pH and solvent are selected for obtaining a hydrate having high stability.
• the stability of the hydrate of the compound of formula I prepared by a solvent having a pH outside the range of 2.0 to 5.0 or selected from a solvent other than the present invention is markedly lowered.
• the hydrate of the compound of formula I is significantly more stable than the hydrate having a moisture content of more than 30% or less than 8.0% at a moisture content of 8.0% to 30%.
• the hydrate A (1.07 mmol, 1.00 g) of the compound of the formula I obtained in Example 2 was dissolved in 12 ml of DMF, cooled to below 0 ° C in an ice bath, and diisopropylethylamine (0. 22 g 1 ) was added. . 67mmol ) while maintaining the temperature at 0 ° C, slowly add MKC-8 ( 1- [4- [5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoyloxy] -1H- 1, 2 3-benzotriazole) (0. 53g 1. 14mmol), the reaction was heated to 2-6 ° C, and the reaction was carried out for 4 hours.
• the compound of the formula II is prepared by using the hydrate of the compound of the formula I B C D H N S.
• the synthesis of the compound of the formula II is carried out from the compound of the formula I by reference to the micafungin synthesis process of 2004014879.
• Comparative example 1 Preparation of a compound of formula II using a hydrate of formula I having a moisture content of less than 8%. Referring to the micafungin synthesis process of WO2004014879, the synthesis of a compound of formula II is carried out from a compound of formula I.
• the reaction was heated to 2-6 ° C, and the reaction was carried out for 4 hours. After the completion of the reaction, 60 ml of ethyl acetate was added to each reaction solution, and the mixture was further stirred for 1 hour, and filtered to obtain micafungin diisopropylethylamine salt.
• the salt obtained above was washed with 30 ml of acetone and 30 ml of ethyl acetate, and filtered. The residual organic solvent was removed by vacuum drying micafungin diisopropylethylamine salt. The purity results and the synthetic yield results of micafungin diisopropylethylamine salt were analyzed by HPLC.
• the compound of formula II is prepared by using the hydrate of the compound of formula I in Example 1.
• the hydrate (1.07 mmol, 1.00 g) of the compound of the formula I obtained in Example 1 was obtained. Dissolve in F12ml, cool to below 0 °C in an ice bath, add diisopropylethylamine (0.22g, 1.67mmol), keep the temperature at 0 °C, slowly add MKC-8 ( 1- [4- [ 5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoyloxy]-1H-1,2,3-benzotriazole) (0. 53g, 1. 14mmol), The reaction was warmed to 2-6 ° C, and the reaction was carried out for 4 hours.

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